1. Field of the Invention
The present invention relates to novel multivalent polymeric amyloid-beta-binding substances composed of several interconnected substances which per se already have amyloid-beta-binding properties, and to the use of these substances, referred to hereinbelow as “polymers”, in particular in medicine.
2. Discussion of Background Information
Owing to the demographic development in the coming decades, the number of persons who suffer from age-related diseases will increase. Alzheimer's disease (AD, Alzheimer's dementia, Latin=morbus Alzheimer) must be mentioned in particular in this context.
No active substance or medicament exists to date that acts against the causes of AD. The medicaments which have been approved and employed to date alleviate some of the symptoms which occur in Alzheimer's dementia, but are not capable of slowing down the progression of the disease or of bringing about a recovery. Some substances exist which have been successful in animal experiments in the prevention, but not (necessarily) in the treatment of AD. Active substances against neurodegenerative diseases are known from DE 10 2006 015 140 A1.
One feature of Alzheimer's disease are extracellular deposits of amyloid-beta peptide (A-beta peptide, Aβ or Aβ peptide). These deposits of the A-beta peptide in plaques can typically be found post mortem in the brains of AD patients. This is why various forms of the A-beta peptide—such as, for example, fibrils—are held responsible for the development and progression of the diseases. In addition, the small, freely-diffusible A-beta oligomers have been considered for some years to be the main cause for the development and progress of AD.
A-beta monomers, being units of the A-beta oligomers, are constantly being generated in the human body and, probably, are not toxic per se. Indeed, it is possible that monomers exert a positive function. Depending on their concentration, A-beta monomers can undergo random association. The concentration depends on their rate of generation and degradation in the body. If, with increasing age, the concentration of A-beta monomers in the body increases, spontaneous association of the monomers to give rise to A-beta oligomers becomes more and more probable. The resulting A-beta oligomers might multiply analogously to prions and, ultimately, result in Alzheimer's disease.
An important difference between the prevention and treatment or indeed cure of AD is the fact that prevention might possibly already be achieved by preventing the first A-beta oligomers from being formed. To this end, some few A-beta ligands with low affinity and with selectivity for the A-beta oligomers will suffice.
The formation of A-beta oligomers from a large number of monomers is a high-order reaction and, therefore, dependent to a higher power of the A-beta monomer concentration. Thus, even a small reduction in the active A-beta monomer concentration will lead to the formation of the first A-beta oligomers being prevented. It is probable that the—rather preventative—therapeutic concepts and substances which are currently being developed are based on this mechanism.
In the treatment of AD, however, one will have to depart from a completely different situation. In this case, A-beta oligomers or, possibly, even larger polymers or fibrils exist, which multiply by prion-like mechanisms. This multiplication, however, is a low-order reaction and dependent from the A-beta monomer concentration to a minor degree only.
The prior-art substances reduce the A-beta monomer and/or oligomer concentration in very different ways. Thus, for example, gamma-secretase modulators are known which have been employed for preventative purposes in animal experiments.
WO 02/081505 A2 discloses various sequences of D-amino acids which bind to A-beta peptides. These D-amino acid sequences bind to amyloid-beta peptides with a dissociation constant (KD value) of 4 μM.
WO 2011/147797 A2 discloses hybrid compounds composed of aminopyrazols and peptides, which hybrid compounds prevent the oligomerization of A-beta.
Compounds which interact with A-beta peptides are disclosed from DE 10 2008 037 564 A1, DE 696 21 607 T2 or DE 10 2010 019 336 A1. The binding of a multivalent polymer to two binding partners is described in WO 2008/116293 A1.
In the case of many substances which have demonstrated positive results in animal experiments it has not been possible to confirm this activity in clinical studies on humans. Clinical phase-II and III studies only allow the treatment of humans where AD has been diagnosed unambiguously. In this case, a small reduction of the A-beta monomer concentration will no longer suffice for preventing that the already existing A-beta oligomers give rise to even more of the same, for example by a prion-like mechanism. The multiplication of the A-beta oligomers or, even better, their destruction or neutralization is, however, essential to influence the pathogenesis.
To date, Alzheimer's dementia is mainly diagnosed by neuropsychological tests, by experiments on persons where symptoms of dementia have been identified. However, it is known that A-beta oligomers and the subsequently following fibrils and plaques originate up to 20 years before symptoms are observed in the patient's brain, and may already have caused irreversible damage. However, it has not been possible to date to diagnose AD before the onset of symptoms.
Therefore, there remains a need for novel compounds (active substances) which bind to A-beta oligomers in a highly specific manner and with high affinity, therefore preventing their multiplication. It is intended that these compounds do not cause any effects with undesired side-effects, in particular no immune reaction. It is furthermore intended that the compounds recognize, completely destroy and/or prevent the (prion-like) multiplication of, toxic A-beta oligomers and therefore even the small, freely-diffusible oligomers even at low concentrations.
Furthermore, there is also a need for novel compounds which can be employed as probes for recognizing and labeling A-beta oligomers, in particular when these oligomers are only present at low concentrations.